B-cell malignancies are the sixth most common cause of cancer-related deaths in the United States. While some aggressive lymphomas may be cured with cytotoxic therapy, most patients are incurable with current therapy. Novel effective therapies are therefore needed to treat these patients. B-lymphocyte stimulator (BLyS) is a TNF-family molecule that promotes B-cell survival and is a key regulator of peripheral B-cell populations. It binds to three receptors - BCMA, TACI and BAFF-R. We have shown that malignant B- cells can produce BLyS and that cells from patients with B-cell malignancies commonly express TACI and BAFF-R. We have found that BLyS protects malignant B-cells from apoptosis and that serum BLyS levels in lymphoma patients correlate with response to therapy and overall survival. We have also found that patients with a family history of B-cell malignancies have a higher incidence of elevated serum BLyS levels and this is associated with a polymorphism in the BLyS promoter region. It is therefore anticipated that molecules that inhibit the effects of BLyS will provide a novel strategy to treat patients with B-cell malignancies. TACI-Fc is a recombinant fusion protein containing the extracellular, BLyS-binding portion of the receptor TACI and the modified Fc portion of human lgG1. TACI-Fc acts as an antagonist to BLyS by working as a decoy receptor that binds BLyS thereby potentially decreasing the pro-survival signal in B-cell malignancies. In collaboration with ZymoGenetics and Serono, we have designed a phase I clinical trial and a subsequent extension study to evaluate the optimal dose and potential activity of TACI-Fc. In this proposal, we plan to determine the biological effects of BLyS inhibition on malignant B-cells in patients with non-Hodgkin lymphoma and chronic lymphocytic leukemia and to evaluate whether this will lead to an improved clinical outcome for patients with B-cell malignancies.